tbuckley/cabot-search huggingface dataset:
Abstract 3115: Predicting in-depth mechanism of action of cancer drugs
Authors: Sanju Sinha, Neelam Sinha, Eytan Ruppin
Journal: Cancer Research (2023)

Abstract Knowing a drug’s mechanism of action (MOA) is essential for its clinical success by selecting the best indications, likely responders, and combinations. Yet knowledge of many drugs’ MOA remains lacking. Here we present DeepTarget, a computational tool for deep characterization of cancer drugs’ MOA by integrating existing large-scale genetic and drug screens. Spanning ∼1500 drugs across ∼18K possible target genes, DeepTarget predicts: (1) a drug’s primary target(s), (2) whether it specifically targets the wild-type or mutated target forms, and (3) the secondary target(s) that mediate its response when the primary target is not expressed. We first tested and successfully validated DeepTarget in a total of eleven unseen gold-standard datasets, with an average AUC of 0.82, 0.77, and 0.92 for the above three prediction abilities, respectively. We then proceed to use it in a wide range of applications: First, we find that DeepTarget’s predicted specificity of a drug to its target is strongly associated with its success in clinical trials and is higher in its FDA-approved indications. Second, DeepTarget predicts candidate drugs for targeting currently undruggable cancer oncogenes and their mutant forms. Finally, DeepTarget predicts new targets for drugs with unknown MOA and new secondary targets of approved drugs. Taken together, DeepTarget is a new computational framework for accelerating drug prioritization and its target discovery by leveraging large-scale genetic and drug screens. Citation Format: Sanju Sinha, Neelam Sinha, Eytan Ruppin. Predicting in-depth mechanism of action of cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3115.
Abstract 511: A small molecule CET019 inhibits progression of triple negative breast cancer
Authors: Arpit Dheeraj, Dhanir Tailor, Fernando Jose Marques, Benedikt Grau, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, which accounts for 15-20% of total diagnosed breast cancer cases with high rates of metastasis and recurrence. Metastatic breast cancer remains one of the leading causes of cancer related mortality in women. The majority of women with this disease relapse after curative-intent therapy for early breast cancer; while a smaller proportion present with distant metastases at initial diagnosis. Our efforts of developing effective therapies for TNBC have identified CET019, a novel small molecule that effectively inhibits the growth of breast cancer cells. We found that CET019 impedes the clonogenic potential and growth of triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, SUM159 and 4T1). CET019 treatment induces the G2/M phase cell cycle arrest in TNBC cells. Moreover, the mouse xenograft study with different TNBC models, found that CET019 inhibits growth and progression compared to vehicle control group. Metastatic nodules in the lungs were inhibited by CET019 compared to control group. Collectively, our in vitro and in vivo experiments, provide foundation to further develop CET019 as a potential drug candidate to treat patients with TNBCs. Citation Format: Arpit Dheeraj, Dhanir Tailor, Fernando Jose Marques, Benedikt Grau, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra. A small molecule CET019 inhibits progression of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 511.
Abstract 5148: Interrogating immuno-oncological interactions in the tumor microenvironment
Authors: Ben Patterson, g-Yi Chen, Nicolas Fernandez, Leiam Colbert, Jiang He
Journal: Cancer Research (2023)

Abstract Single-cell RNA sequencing is a powerful and innovative tool for assessing individual cancer prognoses and outcomes; however, the process of generating this data typically destroys the spatial complexity of the tumor microenvironment. Understanding the spatial complexities within cancer provides crucial information for evaluating individual tumor development and progression. Vizgen’s MERSCOPETM Platform, built on Multiplexed Error-Robust Fluorescence in situ Hybridization (MERFISH) technology, enables the direct profiling of the spatial organization of intact tissue with subcellular resolution. Here, we present a Pan-Cancer approach to demonstrate the MERSCOPE’s ability to characterize breast, colon, prostate, ovarian, lung, and skin cancers from human clinical samples. Specifically, using a 500-gene panel to assess the canonical signaling pathways of cancer, cancer type-specific genes, select immune genes, proto-oncogenes, and tumor-suppressor genes, we show that the MERSCOPE was able to spatially profile gene expression across multiple tumor types. We utilized the Vizgen Cell Boundary Stain kit to generate a molecular and cellular atlas of individual patient tumors by clustering cells based on gene expression and mapping their spatial organization. To gather insight into immuno-oncological interactions and their effect on gene expression across these tumor types, we performed a neighborhood analysis to determine how proximity to immune cells altered gene expression in tumor cells, and vice versa. We found significant gene expression changes in MHC activation and downstream pathways in immune cells located nearest to tumor cells; in tumor cells nearest to immune cells, we identified increased expression of genes related to immune response mediation and inflammation. Furthermore, we compared the annotated immune cell populations across the various cancer types to observe differences in gene expression. Here, we used publicly available single-cell RNA-sequencing data to impute gene expression for these immune cell populations. This analysis demonstrated the transcriptional variation possible in identical immune cell types that are acting in different tissue contexts. Notably, we were able to map and catalogue different patterns of gene expression relating to inflammation, immune signaling, and immune cell exhaustion. These findings demonstrate how the MERSCOPE platform can provide deep insights into the complex heterogeneity observed between different tumor types and tissues. Citation Format: Ben Patterson, g-Yi Chen, Nicolas Fernandez, Leiam Colbert, Jiang He. Interrogating immuno-oncological interactions in the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5148.
Abstract 985: An innovative spatial biology biomarker discovery approach to enable acceleration of drug development
Authors: Jason W. Reeves, Esperanza Anguiano, Vikram Devgan, Nicholas Confuorto, Joachim Schmid, Yan Liang, Joseph Beechem
Journal: Cancer Research (2023)

Abstract Biomarker development in the clinical trial setting is frequently limited by the availability of small tissue specimens, such as core needle biopsies. To enable forward and reverse translational assays to best understand patient-specified biomarkers, high-plex assays which can be performed on individual slides are critical. We’ve developed the GeoMx® Digital Spatial Profiler (DSP) and CosMx™ Spatial Molecular Imager (SMI) to allow researchers to explore more hypotheses simultaneously from standard histopathology slides. We demonstrate on standard FFPE sections how the GeoMx and CosMx platforms integrate within the context of biomarker discovery. The GeoMx platform can resolve transcriptome-wide RNA expression profiles or 150+ protein targets from tissue structures selected by pathological review. The CosMx platform allows subcellular profiling of up to 1000 RNA transcripts or 64 proteins from a single slide. We demonstrate the integration of GeoMx and CosMx into a multi-modal approach to how high-plex spatial platforms can complement conventional diagnostic assays for translational research. This includes integration with downstream analytical tools such as digital pathology suites as well as machine learning approaches to model patient outcomes. Spatial technologies, such as GeoMx and CosMx, present groundbreaking opportunities for improving accuracy in biomarker discovery and for providing rich biological insight beyond low-plex profiling approaches. Citation Format: Jason W. Reeves, Esperanza Anguiano, Vikram Devgan, Nicholas Confuorto, Joachim Schmid, Yan Liang, Joseph Beechem. An innovative spatial biology biomarker discovery approach to enable acceleration of drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 985.
Abstract 249: A novel suite of enzyme mixes enable robust hybrid capture sequencing from low quality FFPE DNA
Authors: Margaret R. Heider, Jian Sun, Brittany S. Sexton, Bradley W. Langhorst, Andrew Gray, Lauren Higgins, Lixin Chen, Lynne Apone, Thomas C. Evans, Nicole M. Nichols, Pingfang Liu
Journal: Cancer Research (2023)

Abstract In cancer genomics, a common source of DNA is formalin-fixed, paraffin-embedded (FFPE) tissue from patient surgical samples, where in most cases high-quality fresh or frozen tissue samples are not available. FFPE DNA poses many notable challenges for preparing NGS libraries, including low input amounts and highly variable damage from fixation, storage, and extraction methods. Due to the high cost of sequencing and variability of coverage, regions of interest are often specifically enriched using hybrid capture-based approaches, but these methods require a high input of diverse, uniform DNA library to achieve the coverage required for somatic mutation identification in tumor samples. We developed a new DNA repair enzyme mix, enzymatic fragmentation mix, and library amplification PCR master mix, optimizing the activities of these mixes using FFPE samples ranging from DIN 1.8 to 6.8 to maximize yield, WGS library quality, and target enrichment library performance. Combining DNA damage repair and a novel enzymatic fragmentation mix upstream of library preparation reduced the false positive rate in somatic variant detection by repairing damage-derived mutations, and also improved the library yield, quality metrics (including mapping, chimeras, and properly-paired reads), complexity, coverage uniformity, and hybrid capture library quality metrics. The new PCR master mix boosts the library yield without compromising library quality in FFPE-derived samples, allowing flexibility in the PCR cycles used to accommodate high-throughput processing of FFPE samples of highly varied quality. This library prep workflow was evaluated with multiple sequencing platforms including Illumina, MGI, and Element Biosciences. This new suite of enzyme mixes allows even highly damaged FFPE samples to achieve high-quality libraries with sufficient input for hybrid capture. Increasing the useable reads and coverage enables robust detection of somatic variants as demonstrated using both reference standard DNA and patient-derived FFPE samples. Finally, the use of enzymatic fragmentation and a flexible PCR master mix make this FFPE library prep workflow compatible with high-throughput and automation-based workflows. Citation Format: Margaret R. Heider, Jian Sun, Brittany S. Sexton, Bradley W. Langhorst, Andrew Gray, Lauren Higgins, Lixin Chen, Lynne Apone, Thomas C. Evans, Nicole M. Nichols, Pingfang Liu. A novel suite of enzyme mixes enable robust hybrid capture sequencing from low quality FFPE DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 249.
Abstract 1458: The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity
Authors: Félix Després, Damien Robichaud, Brandon Hannay, Gilles A. Robichaud
Journal: Cancer Research (2023)

Abstract Breast cancer metastasis is responsible for 90% of deaths associated with the disease. The understanding of mechanisms driving metastasis is thus vital to mitigate mortality rates and improve patient outcome. One of these mechanisms essential for breast cancer malignancy is the activation of the Nuclear Factor of Activated T cells (NFAT) pathway. Recently, we have reported that the PAX5 transcription factor induces breast cancer cell epithelialization, which in turn extinguishes mesenchymal transitioning, malignant features, and tumor progression. Our preliminary findings also suggests that PAX5 may negatively regulate NFAT-dependant pathways to modulate breast processes and potentially disease progression. We therefore hypothesized that PAX5 suppressed breast cancer malignancy through the targeted inhibition of the pro-malignant NFAT pathway. Using breast cancer cell models, we conditionally modulated PAX5 levels by transfection and recombinant expression to characterize PAX5-induced inhibition of the NFAT activation pathway and its mechanisms of action. Technically, expression levels for NFAT members (1 to 5) and their regulators (ex: calcium mobilization, specific kinases, and phosphatases) were assessed using RT-qPCR and Western blotting. NFAT activation was also studied through the analysis of cellular compartmentalization, reporter gene assays, and microscopy. We observed that PAX5 suppressed overall NFAT-dependant transcriptional activity in breast cancer cells through various mechanisms depending on the type of breast cancer models. We also found that although elevated PAX5 expression levels do not alter total NFAT protein levels, PAX5 affects the phosphorylation status of NFAT (activation) through the regulation of NFAT-specific phosphatases and kinases controlling NFAT import and downstream transactivation pro-malignant genes. We also found that PAX5 modulates intracellular calcium mobilization, which is also essential for NFAT activation. Altogether, our findings demonstrate that PAX5 is a potent inhibitor of NFAT-dependant processes essential for in breast cancer malignancy. Interestingly, PAX5-mediated suppression of the NFAT pathway in breast cancer cells is elicited by multiple regulatory mechanisms, which also depend on breast cancer cell type. These studies provide new insight into the molecular pathways governing breast malignancy and disease progression. Further understanding of these mechanisms of action will build the future roadmaps for therapeutic and prognostic interventions. Citation Format: Félix Després, Damien Robichaud, Brandon Hannay, Gilles A. Robichaud. The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1458.
Abstract 2613: Chronic NNAL exposure, mimicking tobacco use in humans, deactivates LKB1 and promotes tumor progression in non-small cell lung cancer
Authors: Tengfei Bian, Lingtao Jin, Chengguo Xing
Journal: Cancer Research (2023)

Abstract Background: LKB1 loss-of-function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss-of-function is associated with patients’ smoking status. We recently discovered that NNAL, a major metabolite of a tobacco specific carcinogen NNK, rapidly induces LKB1 phosphorylation and its loss-of-function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. Such an acute exposure, however, only resulted in moderate enhancement in lung cancer cell migration and chemoresistance. Here we characterized the effects of chronic NNAL exposure, better mimicking human tobacco use, on LKB1 and tumor progression in NSCLC in vitro and in vivo. Methods and Results: Human NSCLC cells with wild type LKB1 (H1299 and H1975) were cultured in the presence of 1 nM NNAL for 3, 6 and 12 months. LKB1 and its signaling pathways were characterized with phenotypes evaluated, including cell proliferation, migration, and chemoresistance. NNAL chronic exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation and the deactivation of its signaling, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss-of-function. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. Conclusion: These results suggest that LKB1 loss-of-function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway. Citation Format: Tengfei Bian, Lingtao Jin, Chengguo Xing. Chronic NNAL exposure, mimicking tobacco use in humans, deactivates LKB1 and promotes tumor progression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2613.
Abstract 3092: Optimization of deferiprone for the treatment of triple-negative breast cancer
Authors: Alexis Johnston, Adegboyega K. Oyelere
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is the leading cause of new cancer cases and the second leading cause of cancer deaths in American women. TNBC is one of the most difficult cancers to treat due to the lack of three receptors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), found in regular forms of breast cancer (BCa). Currently, there is no targeted therapy for TNBC and treatment options to manage this lethal disease include surgery, adjuvant chemotherapy and radiotherapy. A better understanding of TNBC etiology has aided in unraveling the roles of two additional cellular targets - androgen receptor (AR) and histone lysine demethylase (KDM) - in the viability and survival of TNBC. Interestingly, AR overexpression is the most important driver of prostate cancer (PCa). A class of current medications used to treat PCa act as androgen receptor (AR) antagonists (or antiandrogens). It is therefore plausible to repurpose and optimize these antiandrogens for TNBC therapy. The proposed therapeutics are dual-acting antiandrogen-KDM inhibitors. The antiandrogen moiety of these agents will enable TNBC cell-targeting and translocation of the drug into the nucleus where inhibition of KDM will prevent transcription of KDMs that promote tumor. The three pharmacophores of these agents are (i) a surface recognition cap, (ii) a linker, and (iii) an Fe2+-binding group. Two classes of these compounds, alkyl-derivative and benzyl-derivative, vary in the design of the surface recognition cap. To optimize these agents, the linker length is varied from 2-7 methylene groups in each class and the optimal length will be determined through in vitro studies. The compounds are tested on five cancer cell lines: TNBC cell lines (MDA-MB-231, low AR+; and MDA-MB-453, high AR+), and ER+ BCa (MCF-7) while PCa cell lines (LNCaP PCa, AR+; and DU 145, PCa, AR-) serve as controls for AR dependency of the effects of test compounds. Longer linker length compounds exhibited low micromolar cytotoxicity and selectivity for MDA-MB-231 (TNBC) and LNCaP (PCa) cell lines due to the presence of the AR. Western blot analysis on lead compounds supported significant downregulation of AR in MDA-MB-231 cells confirming the predicted mechanism of action. Thus far, the designed dual-acting therapeutics have potential to revolutionize the design of anticancer drugs and improve treatment outcome for TNBC patients. Citation Format: Alexis Johnston, Adegboyega K. Oyelere. Optimization of deferiprone for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3092.
Abstract 5190: Systematic immune-profiling of immune-deficient mouse models: A rational to select ideal host for tumor implantation
Authors: Hervé Luche, Lillia Hadjem, Marielle Mello, Priscilla Canavese, Fabien Angelis, Anais Joachim, Sylvie Bouilly, Frederic Guinut, Frederic Fiore, Bernard Malissen, Ana Zarubica, Erwan Corcuff
Journal: Cancer Research (2023)

Abstract Preclinical tumor oncology research relies historically on the analysis of mouse or human tumor cell lines implanted onto severely immune-deficient mouse models carrying nude, SCID or Rag mutations on different genetical background (C57Bl/6N, BalbC, NMRI, CB17 or NOD). These lines harbor defects in several leukocyte lineages among which Tc, Bc and NKc might be affected. Humanized mice are emerging models that have been transplanted with human cells or tissues (and/or equipped with human transgenes). Currently, the most advanced strains are the nonobese diabetic, severe combined immunodeficiency (NOD-SCID) mouse with complete disruptions in the interleukin-2 (IL-2) common γ-chain (IL2R γ null) receptor (NSG) and BALB/c Rag2−/− IL2R γ null SirpaNOD mice (BRGS).1 Juvenile chimera NSG or BRGS are reconstituted with hematopoietic progenitor cell (HPCs) from human cord blood yielding robust engraftment of a human immune system (HIS).. Recent work showing the binding of human IgG4 to mouse FcgR receptor reducing clinical efficacy of therapeutic antibodies highlights the need to characterize extensively the residual immune system present in these models prior humanization in order to precisely evaluate immunotherapies. In other to fulfill this task, we genetically modified the mouse genome introducing mutations involved in Tc, Bc and NKc development. We then immuno-phenotyped over 20 lines of mouse mutants produced from the same animal house to minimize the impact of microbiota on innate immune cell populations. High content cytometry analysis of BM, spleen, thymus and peripheral blood was performed in a standardized manner. The resource obtained of these immunotypes was used to highlight similarities and differences among these lines across several genetical background. This work has shown instrumental in selecting the most appropriate model to use for humanization followed before tumor implantation. Citation Format: Hervé Luche, Lillia Hadjem, Marielle Mello, Priscilla Canavese, Fabien Angelis, Anais Joachim, Sylvie Bouilly, Frederic Guinut, Frederic Fiore, Bernard Malissen, Ana Zarubica, Erwan Corcuff. Systematic immune-profiling of immune-deficient mouse models: A rational to select ideal host for tumor implantation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5190.